Cannabinoids can have anti-inflammatory effects when they engage the ECS by binding to CB2 receptors. When chronic opioids cause pro-inflammatory responses, CB2 activation can inhibit these responses as well, research published by the American Pain Society has found. Diminishing opioid tolerance is a valuable tool in protecting people from opioid overdose. CB2 activation could play a valuable part in treating opioid dependence and tolerance.
Your CB2 receptors are most commonly found on immune cells.
CB1 receptors are primarily active in your brain, central nervous system, lungs, liver, and kidneys. They are most prominent in the central nervous system, where they interact with neurons.
CB2 activation may also play a role in minimizing stroke symptoms according to research published by the American Heart Association and American Stroke Association. Because inflammation accounts for a large portion of the neural damage caused by strokes, CB2 activation may have a neuroprotective effect on potential stroke victims.
What does the CB2 receptor do?
An important protein in the body’s endogenous cannabinoid system that is heavily involved in the body’s immune system, and plays an important role in fighting inflammation.
Both CB2 and CB1 are g-protein coupled receptors (GPCR) , a large and diverse group of cell membrane receptors, that connect with and activate intracellular messenger proteins of the Gi/Go family. Scientists have not yet elucidated the exact 3D structure of the CB2 protein as they have for CB1, so our understanding of how molecules bind to the CB2 is somewhat limited in comparison to CB1 .
Cannabinoid receptors are an essential component of the body’s endocannabinoid system (ECS). Every function in our bodies requires balance, or homeostasis, to perform at maximum capacity. The ECS, which is made up of a network of endocannabinoid receptors, helps the body maintain homeostasis through its three main components: “messenger” molecules called cannabinoids, the receptors that these molecules bind to, and the enzymes that break them down for the body to synthesize. Pain, stress, appetite, energy metabolism, cardiovascular function, reward and motivation, reproduction, and sleep are all functions that the ECS can modulate.
Where are the CB1 and CB2 receptors located?
The body has two main cannabinoid receptors — the CB1 receptor and the CB2 receptor.
The body’s most studied cannabinoid receptors are cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). While they play slightly different roles in different parts of the body, both receptors are critical to the overall function of the cannabinoid system in the body.
Experimental approach: The [35S]GTPS binding assay was used to determine both the efficacy of cannabidiol and the ability of cannabidiol to antagonize cannabinoid receptor agonists (CP55940 and R-(+)-WIN55212) at the mouse CB1 and the human CB2 receptor.
Key results: This paper reports firstly that cannabidiol displays inverse agonism at the human CB2 receptor. Secondly, we demonstrate that cannabidiol is a high potency antagonist of cannabinoid receptor agonists in mouse brain and in membranes from CHO cells transfected with human CB2 receptors.
Background and purpose: A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB1 and CB2 receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB1 receptors expressed in mouse brain and to human CB2 receptors that have been transfected into CHO cells.
Conclusions and implications: This study has provided the first evidence that cannabidiol can display CB2 receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB2 receptor. The ability of cannabidiol to behave as a CB2 receptor inverse agonist may contribute to its documented anti-inflammatory properties.
It is well known that the CB2 receptor is widespread among cells of the immune system. Table 3 provides the literature associated with the expression of the CB2 receptor in human leukocytes. Every cell type that has been investigated was found to express both mRNA and protein in at least one report. However, there is conflicting data associated with a few cell types. For example, there is no consensus in the literature regarding the presence of the CB2 receptor in human neutrophils. Of note, not every study was conducted on purified, eosinophil-depleted neutrophils. Given that eosinophils have very abundant amounts of CB2 receptor mRNA, a small number of eosinophils among the neutrophil sample could result in a false positive. This is consistent with the observation that CB2 levels are lower in neutrophils than in eosinophils.
This wide array of CB2 receptor agonists being able to improve IBD in animal models prompted the development of highly selective compounds that could be used to treat the disease in humans. In this regard, a research group synthesized a series of CB2-selective agonists and tested the resulting lead compounds in models of experimental colitis [200, 201]. Intra-peritoneal injection of the agonists was effective at protecting mice against colitis. Of note, a selective compound that is orally effective in experimental colitis was later synthesized .
CB2 expression in immune cells
Synthetic cannabinoids, such as CP 55,940 and WIN 55,212-2, were already available when the CB2 receptor was cloned. They were subsequently shown to be potent CB2 ligands, but also to lack selectivity, as they activate CB1 with comparable efficiency. In this respect, several agonists and antagonists were rapidly developed and made available to the scientific community. The most widely used compounds are the agonist JWH 133, and the antagonists SR144528 and AM630. Still, many compounds display good potency and selectivity towards CB2. Table 2 contains a comprehensive list of those compounds, as well as their binding potency towards human CB2, and in some cases, the other receptors they target.
Atherosclerosis is an inflammatory disease that is characterized by the presence of arterial plaques. These lesions contain immune cells, lipid-laden macrophages (foam cells), cholesterol, smooth muscle cells, and collagen fibres . The physical rupture of the plaques causes the occlusion of arteries, which can lead to tissue infarction. Plaque development is influenced by inflammatory mediators, such as cytokines and chemokines, which are crucial to the recruitment of immune cells to the intima. In this respect, therapies that would downregulate the production of these mediators could reduce the progression of atherosclerotic lesion development. Since the CB2 receptor is known to decrease the production of numerous chemokines and to inhibit leukocyte migration in vitro and in vivo, it emerged as a potential target to treat atherosclerosis.
Potential in inflammatory bowel disease
The pattern of CB2 receptor expression among human tissues is consistent between studies. More groups have reported the presence of the CB2 receptor mRNA and protein in the human spleen  and tonsils . Moreover, the high level of CB2 expression in human immune tissues was also reported in murine and rodent spleen [37, 50–56] and thymus [37, 54].